Eye uveitis is a kind of immunogenicity disease which is intractable and common in clinical. The disease can damage the blood-ocular barrier, and cause hyperplasia of adjacent tissues within the eyes, thereby inducing cataracts, macular edema, secondary glaucoma, and finally ocular tissue damage. The disease is of high blinding-rate, seriously affect the visual quality and life quality of patients. In western countries, about 35% of uveitis patients exhibit varying degrees of visual impairment. The blinding-rate of domestic uveitis patients is 18.76%.
Currently, the treatment of uveitis mainly is local or systemic use of non-steroidal anti-inflammatory drugs, hormones and immunosuppressive agents. However, hormones or immunosuppressive agents inevitably induce some serious side effects, such as cataracts, glaucoma, infections, and renal toxicity; while non-steroidal anti-inflammatory drugs have strong local irritation, and large molecular weight, therefore, the local effective concentration of drug in the eye tissue is, to some extent, limited due to the low permeability of the eye barrier. In addition, drug screening or symptomatic treatment against a variety of pathological results caused by uveitis such as angiogenesis, hyperblastosis and the like can often only relatively alleviate the symptoms, but can not effectively suppress the primary lesion of uveitis, i.e. sthenic inflammatory reaction.
In recent years, an increasing number of biological agents have been proved in laboratory or clinically to have activity of inhibiting ocular inflammation, including antioxidants (e.g. benfotiamine, N-acetylcysteine, etc.), plant extracts, anti-cytokine monoclonal antibody (such as Daclizumab, a monoclonal anti-IL-2 receptor α subunit antibody, Infliximab, a monoclonal anti-TNF-α antibody) and the like. However, these biological agents have many deficiencies, such as large molecular weight, complex in vitro synthesis, complicated recombinant expression and purification processes during the preparation and endotoxin residue. And the biological activity is prone to be inactivated due to the protein conformational changes and modifications And there are risks of serious complications, such as tissue damage because it has large molecular weight, it is difficult to pass through the blood-ocular barrier, and repeated intravitreal injections or transgenic methods are needed to play the role of anti-inflammation.
When developing effective inhibitors of ocular inflammation, the particularity of the ocular drugs should be sufficiently considered.
Firstly, there are many anatomical and functional barriers in eyes. Systemic administration usually cannot result in a local sufficient concentration of drug in ocular tissue due to the blood-aqueous humor barrier and blood-retina barrier. Theoretically, in topical administration, such as injection in vitreous cavity, it is difficult for any macromolecule larger than 76.5 kDa to penetrate the retina and act on the retinal and choroidal vessel.
Secondly, the solubility of the drugs in the hydrophilic tears, aqueous humor, and vitreous humor is positively correlated to their effects.
Thirdly, for the above major reasons, the bioavailability of ocular drugs is very low. To improve it, the administration concentration of drugs should be increased. However, high concentrations of drugs exhibit significant toxicity, so that high dose cannot be used in either systemic or topical administration.
Fourthly, currently a series of relatively safe endogenous inhibitors for inflammation have been demonstrated. However, due to their relative large molecular weight and complicated spatial conformation, these inhibitors have disadvantages in preparation such as complicated recombinant expression and purification processes, residual endotoxin and so on.
Compared with a variety of currently studied protein inhibitors for inflammation, polypeptide inhibitors for inflammation have many outstanding advantages such as simple synthetic method, readiness to be chemically modified, low immunogenicity, high solubility, high bioavailability, strong tissue penetration, various administration route, low cost and so on.
Therefore, there is an urgent need to develop a small molecule anti-inflammation agent which is safe, effective, and suitable for eye ball tissues.